EP1045695B1 - Use of 9-deoxy-2', 9-alpha-methano-3- oxa-4,5,6- trinor-3, 7-(1',3'-interphenylene) -13,14-dihydro- prostaglandin f 1? to treat peripheral vascular disease - Google Patents

Use of 9-deoxy-2', 9-alpha-methano-3- oxa-4,5,6- trinor-3, 7-(1',3'-interphenylene) -13,14-dihydro- prostaglandin f 1? to treat peripheral vascular disease Download PDF

Info

Publication number
EP1045695B1
EP1045695B1 EP98957487A EP98957487A EP1045695B1 EP 1045695 B1 EP1045695 B1 EP 1045695B1 EP 98957487 A EP98957487 A EP 98957487A EP 98957487 A EP98957487 A EP 98957487A EP 1045695 B1 EP1045695 B1 EP 1045695B1
Authority
EP
European Patent Office
Prior art keywords
peripheral vascular
vascular disease
prostaglandin
interphenylene
trinor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP98957487A
Other languages
German (de)
French (fr)
Other versions
EP1045695A1 (en
Inventor
James W. Crow
Shelmer D. Blackburn, Jr.
Robert Roscigno
Michael Wade
Gilles Cloutier
Martine Rothblatt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
United Therapeutics Corp
Original Assignee
United Therapeutics Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by United Therapeutics Corp filed Critical United Therapeutics Corp
Publication of EP1045695A1 publication Critical patent/EP1045695A1/en
Application granted granted Critical
Publication of EP1045695B1 publication Critical patent/EP1045695B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention relates to the use of 9-deoxy-2',9- ⁇ -methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene) - 13,14-dihydro-prostaglandin F 1 (hereafter "UT-15") to manufacture a medicament to treat peripheral vascular disease and kits for this purpose.
  • UT-15 9-deoxy-2',9- ⁇ -methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene) - 13,14-dihydro-prostaglandin F 1
  • the compound UT-15 is a known compound disclosed in U.S. Patent No. 4,306,075 in example 33.
  • UT-15 is a synthetic analog of epoprostenol, a prostaglandin F 1 .
  • the activities ascribed to the various compounds of this patent include inhibition of platelet aggregation, reduction of gastric secretion, and bronchodilation. It is indicated that the compounds of this patent have useful application as anti-thrombotic agents, anti-ulcer agents, and anti-asthma agents.
  • U.S. Patent No. 5,153,222 discloses the use of UT-15 and related compounds to treat pulmonary hypertension.
  • Prostaglandin E 1 has been found to increase walking distance in a small but statistically significant group of patients with peripheral arterial occlusive disease. However, since this drug is rapidly inactivated in the lungs, it must be administered intra-arterially, which leads to numerous harmful side effects. See Belch et al., Circulation , 95(9): 2298-2302 (1997). Belch further discloses the use of AS-013, a prostaglandin E 1 prodrug, to treat peripheral arterial occlusive disease, presenting as intermittent claudication.
  • UT-15 is especially well suited for the treatment of peripheral vascular disease compared to other prostaglandin-type compounds because it is not degraded when it passes through the lungs, it has a long biological half-life, it has potent peripheral vasodilatory properties, it is a highly potent platelet aggregation inhibitor, and it inhibits the release of vasoconstrictive substances.
  • it is an object of the present invention to provide an improved treatment for peripheral vascular disease comprising administering to a subject in need thereof an effective amount of UT-15 and pharmaceutically acceptable salts and acid derivatives thereof, as well as kits for accomplishing this purpose.
  • the present invention relates to a medicament for treatment of peripheral vascular disease, including peripheral arterial occlusive disease and intermittent claudication in a human being, in need thereof comprising an effective amount of UT-15 and/or its pharmaceutically acceptable salts and acid derivatives thereof.
  • kits for accomplishing such treatment comprising (i) an effective amount of UT-15, its pharmaceutically acceptable salts, and/or acid derivatives thereof, (ii) one or more pharmaceutically acceptable carriers and/or additives, and (iii) instructions for use in treating peripheral vascular disease.
  • instructions for use shall mean any FDA-mandated labelling, instructions, or package inserts that relate to the administration of UT-15 for the purpose of treating peripheral vascular disease.
  • instructions for use may include, but are not limited to, indications for peripheral vascular disease, identification of specific symptoms of peripheral vascular disease that can be ameliorated by UT-15, and recommended dosage amounts for subjects suffering from peripheral vascular disease.
  • acid derivative is used herein to describe C1-4 alkyl esters and amides, including amides wherein the nitrogen is optionally substituted by one or two C1-4 alkyl groups.
  • the invention also includes bioprecursors or "pro-drugs" of UT-15, that is, compounds which are converted in vivo to UT-15 or its pharmaceutically active derivatives thereof.
  • the present invention extends to non-physiologically acceptable salts of UT-15 which may be used in the preparation of the pharmacologically active compounds of the invention.
  • the physiologically acceptable salts of UT-15 include salts derived from bases.
  • Base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.
  • Quaternary ammonium salts can be formed, for example, by reaction with lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, with dialkyl sulphates, with long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides, and with aralkyl halides, such as benzyl and phenethyl bromides.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulphates with long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides
  • aralkyl halides such as benzyl and phenethy
  • a daily dose per patient for the treatment of peripheral vascular disease is in the range 25 ⁇ g to 250 mg; typically from 0.5 ⁇ g to 2.5 mg, preferably from 7 ⁇ g to 285 ⁇ g, per day per kilogram bodyweight.
  • an intravenous dose in the range 0.5 ⁇ g to 1.5 mg per kilogram bodyweight per day may conveniently be administered as an infusion of from 0.5 ng to 1.0 ⁇ g per kilogram bodyweight per minute.
  • a preferred dosage is 10 ng/kg/min.
  • Infusion fluids suitable for this purpose contain, for example, from 10 ng to 10 ⁇ g per milliliter.
  • Ampoules for injection contain, for example, from 0.1 ⁇ g to 1.0 mg and orally administrable unit dose formulations, such as tablets or capsules, contain, for example, from 0.1 to 100 mg, typically from 1 to 50 mg.
  • a single unit dose formulation may be administered.
  • physiologically acceptable salts the weights indicated above refer to the weight of the active compound ion, that is, the ion derived from UT-15.
  • UT-15 and its physiologically acceptable salts and acid derivatives are typically admixed with, inter alia, an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the active compound.
  • One or more of UT-15 and/or its physiologically acceptable salts or acid derivatives may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy for admixing the components.
  • UT-15 pharmacologically active substances
  • other pharmacologically active substances may be present in the formulations of the present invention which are known to be useful for treating peripheral vascular disease.
  • the compounds of the invention may be present in combination with trental, a substance known to increase red blood cell deformability.
  • formulations of the invention include those suitable for oral, inhalation (in solid and liquid forms), rectal, topical, buccal (e.g. sub-lingual), parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular form of UT-15, or the physiologically acceptable salt or acid derivative thereof, which is being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of UT-15 or a physiologically acceptable salt or acid derivative thereof; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients).
  • the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising UT-15, or a physiologically acceptable salt or acid derivative thereof, in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of UT-15, or a physiologically acceptable salt or acid derivative thereof, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood. Injectable formulations according to the invention generally contain from 0.1 to 5% w/v of active compound and are administered at a rate of 0.1 ml/min/kg.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing UT-15, or a physiologically acceptable salt or acid derivative thereof, with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the active compound is generally present at a concentration of from 0.1 to 15% w/w, for example, from 0.5 to 2% w/w.
  • Formulations for transdermal administration may be delivered by iontophoresis (see, for example, Pharmaceutical Research 3(6), 318, (1986)) and typically take the form of an optionally buffered aqueous solution of UT-15 or of a salt or acid derivative thereof.
  • Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.
  • UT-15 has three features in particular which make it well suited for treating peripheral vascular disease. Those features are (1) its vasodilation effect, (2) its inhibition of platelet function, and (3) its cytoprotective effect. In addition to having a potent vasodilation effect, the present inventors believe that one important aspect of an effective treatment for peripheral vascular disease is that the active ingredient should be able to inhibit platelet function, which may be an exacerbating factor in peripheral vascular disease. UT-15 exhibits this pharmacological profile.
  • Tests have been performed which support the use of UT-15 to treat peripheral vascular disease.
  • intravenous boluses 0.32-3.2 ⁇ g/kg
  • 10-minute infusions of UT-15 produced dose-dependent decreases in mean arterial blood pressure.
  • intravenous infusions of UT-15 (0.1-3.0 ⁇ g/kg/min) for four hours produced dose-dependent decreases in mean total peripheral vascular resistance.

Abstract

An improved treatment for peripheral vascular disease is described using 9-deoxy-2',9- alpha -methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin F1.

Description

FIELD
The invention relates to the use of 9-deoxy-2',9-α-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene) - 13,14-dihydro-prostaglandin F1 (hereafter "UT-15") to manufacture a medicament to treat peripheral vascular disease and kits for this purpose.
BACKGROUND
The compound UT-15 is a known compound disclosed in U.S. Patent No. 4,306,075 in example 33. UT-15 is a synthetic analog of epoprostenol, a prostaglandin F1. The activities ascribed to the various compounds of this patent include inhibition of platelet aggregation, reduction of gastric secretion, and bronchodilation. It is indicated that the compounds of this patent have useful application as anti-thrombotic agents, anti-ulcer agents, and anti-asthma agents.
U.S. Patent No. 5,153,222 discloses the use of UT-15 and related compounds to treat pulmonary hypertension.
Prostaglandin E1 has been found to increase walking distance in a small but statistically significant group of patients with peripheral arterial occlusive disease. However, since this drug is rapidly inactivated in the lungs, it must be administered intra-arterially, which leads to numerous harmful side effects. See Belch et al., Circulation, 95(9): 2298-2302 (1997). Belch further discloses the use of AS-013, a prostaglandin E1 prodrug, to treat peripheral arterial occlusive disease, presenting as intermittent claudication.
Okuda et al., Prostaglandins, 52(5): 375-384 (November 1996) showed that beraprost sodium, a stable analogue of prostaglandin I2, increased the cross-sectional area and the blood flow index of the dorsal pedis artery in non-insulin dependent diabetes patients. In addition, Okuda showed an increase in the dermal microcirculatory blood volume of these patients.
Patterson et al., Amer. J. of Cardiology, 75(1995): 26A-33A, have shown the vasodilator effects of UT-15 in patients with class III or class IV heart failure.
SUMMARY
The present inventors discovered that UT-15 is especially well suited for the treatment of peripheral vascular disease compared to other prostaglandin-type compounds because it is not degraded when it passes through the lungs, it has a long biological half-life, it has potent peripheral vasodilatory properties, it is a highly potent platelet aggregation inhibitor, and it inhibits the release of vasoconstrictive substances.
Accordingly, it is an object of the present invention to provide an improved treatment for peripheral vascular disease comprising administering to a subject in need thereof an effective amount of UT-15 and pharmaceutically acceptable salts and acid derivatives thereof, as well as kits for accomplishing this purpose.
DETAILED DESCRIPTION
The present invention relates to a medicament for treatment of peripheral vascular disease, including peripheral arterial occlusive disease and intermittent claudication in a human being, in need thereof comprising an effective amount of UT-15 and/or its pharmaceutically acceptable salts and acid derivatives thereof.
The present invention also relates to kits for accomplishing such treatment comprising (i) an effective amount of UT-15, its pharmaceutically acceptable salts, and/or acid derivatives thereof, (ii) one or more pharmaceutically acceptable carriers and/or additives, and (iii) instructions for use in treating peripheral vascular disease.
As used herein, the phrase "instructions for use" shall mean any FDA-mandated labelling, instructions, or package inserts that relate to the administration of UT-15 for the purpose of treating peripheral vascular disease. For example, instructions for use may include, but are not limited to, indications for peripheral vascular disease, identification of specific symptoms of peripheral vascular disease that can be ameliorated by UT-15, and recommended dosage amounts for subjects suffering from peripheral vascular disease.
The term "acid derivative" is used herein to describe C1-4 alkyl esters and amides, including amides wherein the nitrogen is optionally substituted by one or two C1-4 alkyl groups.
The invention also includes bioprecursors or "pro-drugs" of UT-15, that is, compounds which are converted in vivo to UT-15 or its pharmaceutically active derivatives thereof.
Further aspects of the present invention are concerned with the use of UT-15, or a pharmaceutically acceptable salt or acid derivative thereof, in the manufacture of a medicament for the treatment of peripheral vascular disease
The present invention extends to non-physiologically acceptable salts of UT-15 which may be used in the preparation of the pharmacologically active compounds of the invention. The physiologically acceptable salts of UT-15 include salts derived from bases.
Base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.
Quaternary ammonium salts can be formed, for example, by reaction with lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, with dialkyl sulphates, with long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides, and with aralkyl halides, such as benzyl and phenethyl bromides.
The amount of UT-15, or a physiologically acceptable salt or acid derivative thereof, which is required in a medication or diagnostic aid according to the invention to achieve the desired effect will depend on a number of factors, in particular the specific application, the nature of the particular compound used, the mode of administration, and the condition of the patient. In general, a daily dose per patient for the treatment of peripheral vascular disease is in the range 25 µg to 250 mg; typically from 0.5 µg to 2.5 mg, preferably from 7 µg to 285 µg, per day per kilogram bodyweight. For example, an intravenous dose in the range 0.5 µg to 1.5 mg per kilogram bodyweight per day may conveniently be administered as an infusion of from 0.5 ng to 1.0 µg per kilogram bodyweight per minute. A preferred dosage is 10 ng/kg/min. Infusion fluids suitable for this purpose contain, for example, from 10 ng to 10 µg per milliliter. Ampoules for injection contain, for example, from 0.1 µg to 1.0 mg and orally administrable unit dose formulations, such as tablets or capsules, contain, for example, from 0.1 to 100 mg, typically from 1 to 50 mg. For diagnostic purposes, a single unit dose formulation may be administered. In the case of physiologically acceptable salts, the weights indicated above refer to the weight of the active compound ion, that is, the ion derived from UT-15.
In the manufacture of a medicament or diagnostic aid according to the invention, hereinafter referred to as a "formulation", UT-15 and its physiologically acceptable salts and acid derivatives are typically admixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the active compound. One or more of UT-15 and/or its physiologically acceptable salts or acid derivatives may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy for admixing the components.
In addition to UT-15, other pharmacologically active substances may be present in the formulations of the present invention which are known to be useful for treating peripheral vascular disease. For example, the compounds of the invention may be present in combination with trental, a substance known to increase red blood cell deformability.
The formulations of the invention include those suitable for oral, inhalation (in solid and liquid forms), rectal, topical, buccal (e.g. sub-lingual), parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular form of UT-15, or the physiologically acceptable salt or acid derivative thereof, which is being used.
Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of UT-15 or a physiologically acceptable salt or acid derivative thereof; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients).
In general, the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
Formulations suitable for buccal (sub-lingual) administration include lozenges comprising UT-15, or a physiologically acceptable salt or acid derivative thereof, in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of UT-15, or a physiologically acceptable salt or acid derivative thereof, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood. Injectable formulations according to the invention generally contain from 0.1 to 5% w/v of active compound and are administered at a rate of 0.1 ml/min/kg.
Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing UT-15, or a physiologically acceptable salt or acid derivative thereof, with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w, for example, from 0.5 to 2% w/w. Formulations for transdermal administration may be delivered by iontophoresis (see, for example, Pharmaceutical Research 3(6), 318, (1986)) and typically take the form of an optionally buffered aqueous solution of UT-15 or of a salt or acid derivative thereof. Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.
The compounds of the present invention are conveniently prepared by methods the same as or analogous to those described in U.S. Pat. No. 4,306,075 and copending application Serial No. 08/957,726 filed on October 24, 1997.
There are three features of UT-15's pharmacological profile in particular which make it well suited for treating peripheral vascular disease. Those features are (1) its vasodilation effect, (2) its inhibition of platelet function, and (3) its cytoprotective effect. In addition to having a potent vasodilation effect, the present inventors believe that one important aspect of an effective treatment for peripheral vascular disease is that the active ingredient should be able to inhibit platelet function, which may be an exacerbating factor in peripheral vascular disease. UT-15 exhibits this pharmacological profile.
Administration Of UT-15 To Humans Suffering From Peripheral Vascular Disease
Eight patients with moderate to severe peripheral vascular disease (Fontaine Stage IIb-III) were dosed with placebo for a minimum of 30 minutes and then with increasing doses of UT-15 (one hour of dosing at each dose step) until the maximum tolerated dose. Safety was assessed by adverse experience monitoring and clinical laboratory tests.
Common side effects at peak dose were expected and included headache and nausea. No serious adverse events were noted during hospitalization. The most common maintenance dosing level was 10 ng/kg/min. Unaudited data summarized below compare blood flow velocity at baseline and the end of the maintenance dosing period, and include all arteries for which data were available at both time points (up to 12 lower limb arteries in each patient). The data show that blood flow velocity was increased significantly. Acute intravenous UT-15 administration was well-tolerated in patients with moderate to severe peripheral vascular disease. Potentially clinically significant improvement in lower limb blood flow was observed when UT-15 was administered actutely at a maximum tolerated dose. The results are presented below in Tables 1 and 2:
Lower Limb Blood Flow Velocity After Acute Treatment
Baseline End of Treatment % Change from Baseline
64 ± 8 78 ± 9 14 ± 6 (23 ± 9)
Mean in cm/s ± standard error. N = 8 patients.
Summary Of Lower Limb Blood Flow Velocity (BFV) Changes After Acute Treatment
Arteries W/Increase Arteries W/Decrease
In BFV In BFV p (siqn test)
56 19 <.0000001
Administration Of UT-15 To Anesthetized Dogs
Tests have been performed which support the use of UT-15 to treat peripheral vascular disease. In anesthetized dogs, intravenous boluses (0.32-3.2 µg/kg) and 10-minute infusions of UT-15 produced dose-dependent decreases in mean arterial blood pressure. Also, in anesthetized dogs, intravenous infusions of UT-15 (0.1-3.0 µg/kg/min) for four hours produced dose-dependent decreases in mean total peripheral vascular resistance.
Administration of UT-15 To Anesthetized Piglets
Another set of tests has been performed in anesthetized newborn piglets. Intravenous boluses of UT-15 (6 and 12 µg/kg) were shown to abolish hypoxia-induced increases in pulmonary vascular resistance in anesthetized newborn piglets.
It will be apparent to those skilled in the art that various modifications and variations can be made to the compositions and processes of this invention. Thus, it is intended that the present invention cover such modifications and variations, provided they come within the scope of the appended claims and their equivalents.

Claims (7)

  1. Use of an effective amount of 9-deoxy-2', 9-α-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin F1, its pharmaceutically acceptable salts, and/or acid derivatives thereof, for the manufacture of a pharmaceutical composition for treating peripheral vascular disease in a human being.
  2. Use according to claim 1, wherein the 9-deoxy-2',9-α-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin F1 is administered in an orally available form selected from the group consisting of tablets and capsules.
  3. Use according to claim 1, wherein the 9-deoxy-2',9-α-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin F1 is administered by inhalation.
  4. Use according to claim 1, wherein the 9-deoxy-2',9-α-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin F1 is administered subcutaneously.
  5. Use according to claim 1, wherein the peripheral vascular disease is peripheral arterial occlusive disease.
  6. Use according to claim 1, wherein the peripheral vascular disease is intermittent claudication.
  7. Use according to claim 1, wherein the effective amount is 10 ng/kg of body weight/min.
EP98957487A 1997-11-14 1998-11-13 Use of 9-deoxy-2', 9-alpha-methano-3- oxa-4,5,6- trinor-3, 7-(1',3'-interphenylene) -13,14-dihydro- prostaglandin f 1? to treat peripheral vascular disease Expired - Lifetime EP1045695B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US6604997P 1997-11-14 1997-11-14
US66049P 1997-11-14
PCT/US1998/023245 WO1999025357A1 (en) 1997-11-14 1998-11-13 USE OF 9-DEOXY-2', 9-α-METHANO-3- OXA-4,5,6- TRINOR-3, 7-(1',3'-INTERPHENYLENE) -13,14-DIHYDRO- PROSTAGLANDIN F1 TO TREAT PERIPHERAL VASCULAR DISEASE

Publications (2)

Publication Number Publication Date
EP1045695A1 EP1045695A1 (en) 2000-10-25
EP1045695B1 true EP1045695B1 (en) 2004-03-24

Family

ID=22066941

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98957487A Expired - Lifetime EP1045695B1 (en) 1997-11-14 1998-11-13 Use of 9-deoxy-2', 9-alpha-methano-3- oxa-4,5,6- trinor-3, 7-(1',3'-interphenylene) -13,14-dihydro- prostaglandin f 1? to treat peripheral vascular disease

Country Status (12)

Country Link
US (1) US6054486A (en)
EP (1) EP1045695B1 (en)
JP (2) JP3701870B2 (en)
KR (1) KR100638684B1 (en)
CN (1) CN1142781C (en)
AT (1) ATE262336T1 (en)
AU (1) AU1373499A (en)
CA (1) CA2312729C (en)
DE (1) DE69822665T2 (en)
ES (1) ES2214753T3 (en)
WO (1) WO1999025357A1 (en)
ZA (1) ZA9810444B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9255064B2 (en) 2013-10-25 2016-02-09 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US11148997B2 (en) 2014-11-18 2021-10-19 Insmed Incorporated Methods of manufacturing treprostinil and treprostinil derivative prodrugs
US11458098B2 (en) 2019-04-29 2022-10-04 Insmed Incorporated Dry powder compositions of treprostinil prodrugs and methods of use thereof

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU766163B2 (en) 1999-03-05 2003-10-09 Duke University C16 unsaturated fp-selective prostaglandins analogs
EP1354588A1 (en) * 1999-03-18 2003-10-22 United Therapeutics Corporation et al Method for delivering benzindene prostaglandind by inhalation
AU3934000A (en) * 1999-03-18 2000-10-04 United Therapeutics Corporation Inhibitors of endothelin-1 synthesis
US6521212B1 (en) * 1999-03-18 2003-02-18 United Therapeutics Corporation Method for treating peripheral vascular disease by administering benzindene prostaglandins by inhalation
US20020013294A1 (en) 2000-03-31 2002-01-31 Delong Mitchell Anthony Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US20020172693A1 (en) 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US6803386B2 (en) 2002-01-16 2004-10-12 United Therapeutics Corporation Prostacyclin derivative containing compositions and methods of using the same for the treatment of cancer
US7417070B2 (en) 2003-05-22 2008-08-26 United Therapeutics Corporation Compounds and methods for delivery of prostacyclin analogs
DE602004028155D1 (en) * 2003-12-16 2010-08-26 United Therapeutics Corp USE OF TREPROSTINIL FOR THE TREATMENT OF ISCHEMIC LESIONS
US20090124697A1 (en) 2003-12-16 2009-05-14 United Therapeutics Corporation Inhalation formulations of treprostinil
DE602004022982D1 (en) * 2003-12-16 2009-10-15 United Therapeutics Corp USE OF TREPROSTINIL TO IMPROVE THE KIDNEY FUNCTION
US7879909B2 (en) * 2004-04-12 2011-02-01 United Therapeutics Corporation Use of Treprostinil to treat neuropathic diabetic foot ulcers
US8747897B2 (en) 2006-04-27 2014-06-10 Supernus Pharmaceuticals, Inc. Osmotic drug delivery system
CN101495122B (en) 2006-05-15 2011-10-05 联合治疗公司 Treprostinil administration using a metered dose inhaler
DE102006026786A1 (en) 2006-06-07 2007-12-13 Joachim Kern metered dose inhaler
KR20090117781A (en) * 2007-02-09 2009-11-12 유나이티드 세러퓨틱스 코오포레이션 Treprostinil treatment for interstitial lung disease and asthma
ES2630407T3 (en) 2007-12-17 2017-08-21 United Therapeutics Corporation Improved procedure to prepare treprostinil, the active substance in Remodulin®
KR100989093B1 (en) 2008-01-18 2010-10-25 한화제약주식회사 Composition Comprising the Extracts of Branch of Lindera obtusiloba for Prevention and Treatment of Cardiovascular Diseases
EP2300408B1 (en) * 2008-05-08 2016-04-13 United Therapeutics Corporation Process for the preparation of treprostinil monohydrate and its use for storage and shipping
WO2010129757A1 (en) * 2009-05-07 2010-11-11 United Therapeutics Corporation Solid formulations of prostacyclin analogs
WO2011115922A1 (en) 2010-03-15 2011-09-22 United Therapeutics Corporation Treatment for pulmonary hypertension
CN103261142B (en) 2010-06-03 2014-12-10 联合治疗公司 Treprostinil prepatation
JP5580491B2 (en) 2011-03-02 2014-08-27 ユナイテッド セラピューティクス コーポレイション Synthesis of intermediates for the production of treprostinil.
CN103193626B (en) 2012-01-10 2016-05-11 上海天伟生物制药有限公司 Crystal formation of a kind of prostaglandin analogue and its production and use
CN103193627B (en) 2012-01-10 2016-04-20 上海天伟生物制药有限公司 Crystal formation of a kind of prostaglandin analogue and its production and use
CN105164098A (en) 2013-03-14 2015-12-16 联合治疗公司 Solid forms of treprostinil
KR20150128903A (en) 2013-03-15 2015-11-18 유나이티드 세러퓨틱스 코오포레이션 Salts of treprostinil
ES2676447T3 (en) 2013-03-25 2018-07-19 United Therapeutics Corporation Manufacturing process of prostacyclin compounds with binding thiol and pegylated forms
ES2908142T3 (en) 2014-06-13 2022-04-27 United Therapeutics Corp Treprostinil formulations
HU231186B1 (en) 2014-10-08 2021-06-28 CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. Novel process for preparation of treprostinil and its salts
JP6224872B1 (en) 2014-10-20 2017-11-01 ユナイテッド セラピューティクス コーポレイション Synthesis of intermediates to produce prostacyclin derivatives.
US10632129B2 (en) 2014-12-03 2020-04-28 Steadymed Ltd. Preservative-free treprostinil formulations and methods and devices for use with same
JP7220650B2 (en) 2016-09-26 2023-02-10 ユナイテッド セラピューティクス コーポレイション Treprostinil prodrug
US10799653B2 (en) 2017-01-09 2020-10-13 United Therapeutics Corporation Aerosol delivery device and method for manufacturing and operating the same
US11634443B2 (en) 2019-08-23 2023-04-25 United Therapeutics Corporation Treprostinil prodrugs
WO2021211916A1 (en) 2020-04-17 2021-10-21 United Therapeutics Corporation Treprostinil for use in the treatment of intersitial lung disease
JP2023529828A (en) 2020-06-09 2023-07-12 ユナイテッド セラピューティクス コーポレイション fumaryl diketopiperidine prodrug of treprostinil
JP2023553989A (en) 2020-12-14 2023-12-26 ユナイテッド セラピューティクス コーポレイション How to treat diseases with treprostinil prodrugs
CA3209987A1 (en) 2021-03-03 2022-09-09 Hitesh Batra A dry powder composition of trestinil and its prodrug thereof and further comprising comprising (e)-3,6-bis[4-(n-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (fdkp)
WO2023154705A1 (en) 2022-02-08 2023-08-17 United Therapeutics Corporation Treprostinil iloprost combination therapy

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4490537A (en) * 1977-04-19 1984-12-25 The Upjohn Company Enlarged-hetero-ring prostacyclin analogs
US4306075A (en) * 1980-03-28 1981-12-15 The Upjohn Company Composition and process
DE3315356A1 (en) * 1982-04-30 1983-11-17 Ono Pharmaceutical Co. Ltd., Osaka USE OF PROSTAGLANDINE ANALOGS
HU190007B (en) * 1982-05-06 1986-08-28 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu Process for producing new aromatic prostacylin analogues
SU1236380A1 (en) * 1983-07-21 1986-06-07 Областная Клиническая Больница Г.Калинина Method of predicting course of obliterant atherosclerosis of lower extremity
GB8814438D0 (en) * 1988-06-17 1988-07-20 Wellcome Found Compounds for use in medicine
DE4135193C1 (en) * 1991-10-22 1993-03-11 Schering Ag Berlin Und Bergkamen, 1000 Berlin, De

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9255064B2 (en) 2013-10-25 2016-02-09 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US9469600B2 (en) 2013-10-25 2016-10-18 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US10010518B2 (en) 2013-10-25 2018-07-03 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US10526274B2 (en) 2013-10-25 2020-01-07 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US10995055B2 (en) 2013-10-25 2021-05-04 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US11795135B2 (en) 2013-10-25 2023-10-24 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US11148997B2 (en) 2014-11-18 2021-10-19 Insmed Incorporated Methods of manufacturing treprostinil and treprostinil derivative prodrugs
US11458098B2 (en) 2019-04-29 2022-10-04 Insmed Incorporated Dry powder compositions of treprostinil prodrugs and methods of use thereof
US11759425B2 (en) 2019-04-29 2023-09-19 Insmed Incorporated Dry powder compositions of treprostinil prodrugs and methods of use thereof

Also Published As

Publication number Publication date
AU1373499A (en) 1999-06-07
JP3701870B2 (en) 2005-10-05
WO1999025357A1 (en) 1999-05-27
DE69822665T2 (en) 2005-02-17
KR20010015807A (en) 2001-02-26
CN1285748A (en) 2001-02-28
KR100638684B1 (en) 2006-10-27
ES2214753T3 (en) 2004-09-16
CN1142781C (en) 2004-03-24
DE69822665D1 (en) 2004-04-29
CA2312729C (en) 2006-05-23
JP2001522892A (en) 2001-11-20
JP2005225877A (en) 2005-08-25
ZA9810444B (en) 1999-06-24
EP1045695A1 (en) 2000-10-25
CA2312729A1 (en) 1999-05-27
ATE262336T1 (en) 2004-04-15
US6054486A (en) 2000-04-25

Similar Documents

Publication Publication Date Title
EP1045695B1 (en) Use of 9-deoxy-2&#39;, 9-alpha-methano-3- oxa-4,5,6- trinor-3, 7-(1&#39;,3&#39;-interphenylene) -13,14-dihydro- prostaglandin f 1? to treat peripheral vascular disease
US7879909B2 (en) Use of Treprostinil to treat neuropathic diabetic foot ulcers
EP1696932B1 (en) Use of treprostinil to improve kidney functions
US5153222A (en) Method of treating pulmonary hypertension with benzidine prostaglandins
CA2043077C (en) Prostaglandin analogues for use in medicine
EP0347243B1 (en) Prostaglandin analogues for use in medicine
TWI331920B (en) Unit dosage form for relieving or treating constipation in human patients
US6218377B1 (en) Methods for the administration of amifostine and related compounds
CA2060474C (en) Pharmaceutical use
US5028628A (en) Methods of treating pulmonary hypertension
JP7257091B2 (en) Dementia treatment and preventive drug
EP0063773A1 (en) Orally active tolciclate and tolnaftate
IL37889A (en) Compositions for inhibiting indoleamine-n-methyl transferase

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000609

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20020313

RIC1 Information provided on ipc code assigned before grant

Ipc: 7A 61P 9/10 B

Ipc: 7A 61K 31/557 A

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: 7A 61P 9/10 B

Ipc: 7A 61K 31/557 A

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040324

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 69822665

Country of ref document: DE

Date of ref document: 20040429

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040624

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040624

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: UNITED THERAPEUTICS CORPORATION

Free format text: UNITED THERAPEUTICS CORPORATION#1826 R STREET, N.W.#WASHINGTON, DC 20009 (US) -TRANSFER TO- UNITED THERAPEUTICS CORPORATION#1110 SPRING STREET#SILVER SPRING, MD 20910 (US)

Ref country code: CH

Ref legal event code: NV

Representative=s name: BOVARD AG PATENTANWAELTE

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2214753

Country of ref document: ES

Kind code of ref document: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041113

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041113

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041130

ET Fr: translation filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20041228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040824

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: UNITED THERAPEUTICS CORPORATION

Free format text: UNITED THERAPEUTICS CORPORATION#1110 SPRING STREET#SILVER SPRING, MD 20910 (US) -TRANSFER TO- UNITED THERAPEUTICS CORPORATION#1110 SPRING STREET#SILVER SPRING, MD 20910 (US)

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20151111

Year of fee payment: 18

Ref country code: DE

Payment date: 20151110

Year of fee payment: 18

Ref country code: IT

Payment date: 20151124

Year of fee payment: 18

Ref country code: IE

Payment date: 20151109

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20151014

Year of fee payment: 18

Ref country code: FR

Payment date: 20151008

Year of fee payment: 18

Ref country code: AT

Payment date: 20151027

Year of fee payment: 18

Ref country code: BE

Payment date: 20151111

Year of fee payment: 18

Ref country code: SE

Payment date: 20151111

Year of fee payment: 18

Ref country code: NL

Payment date: 20151110

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20161115

Year of fee payment: 19

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161130

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 69822665

Country of ref document: DE

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20161201

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 262336

Country of ref document: AT

Kind code of ref document: T

Effective date: 20161113

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20161113

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20170731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161114

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161113

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161201

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161113

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170601

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161113

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161113

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20161130

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20180507

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040324

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171130

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171130

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20161114